Background: Drug-induced hemolytic anemia (DIHA) is a significant yet underrecognized cause of anemia, resulting from immune-mediated or non-immune-mediated destruction of red blood cells (RBCs) triggered by certain medications. Despite its clinical importance, the prevalence and risk factors of DIHA remain poorly understood due to variability in reporting and diagnostic criteria. This systematic review aims to synthesize current evidence on the prevalence, risk factors, and mechanisms of DIHA to inform clinical practice and future research. Methods: A comprehensive search was conducted across PubMed, Web of Science, SCOPUS, and Science Direct following PRISMA guidelines. Studies published in the last 10 years focusing on DIHA in adult populations were included. Data on prevalence, risk factors, and mechanisms were extracted, and study quality was assessed using the ROBINS-I tool. Results: Eight studies met the inclusion criteria. The prevalence of DIHA varied widely, ranging from 0% to 100%, depending on the drug and patient population. High-risk medications included antibiotics, antifungals, immunosuppressants, and chemotherapeutic agents such as carfilzomib and alectinib. Key risk factors included positive direct antiglobulin test (DAT) results, G6PD deficiency, and erythrocyte membrane alterations. Immune-mediated mechanisms, such as drug-induced autoantibodies, were the most common, though non-immune mechanisms like oxidative stress also played a role. Conclusion: DIHA is a rare but potentially severe adverse drug reaction with significant variability in prevalence and risk factors. Clinicians should maintain a high index of suspicion for DIHA in patients receiving high-risk medications, particularly those with predisposing factors such as G6PD deficiency or autoimmune conditions. Further research is needed to clarify the mechanisms and improve diagnostic and preventive strategies.